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XALACOM (latanoprost and timolol ophthalmic solution (as timolol maleate) Warnings And Precautions

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Warnings And Precautions

General

There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of ocular epithelial surface (see CONSUMER INFORMATION).

There is no or limited experience with latanoprost in inflammatory, neovascular, chronic angle closure or congenital glaucoma, open angle glaucoma in pseudophakic patients and pigmentary glaucoma.

Concomitant therapy: XALACOM (latanoprost and timolol maleate) may interact with other drugs (see DRUG INTERACTIONS). The effect on intraocular pressure or the known effects of systemic beta-adrenergic blocking agents may be exaggerated when XALACOM is given to patients already receiving an oral beta-blocking agent. The use of two local beta-adrenergic blocking agents is not recommended. There have been reports of paradoxical elevations in IOP following the concomitant ophthalmic administration of two prostaglandin analogs. Therefore, the use of two or more prostaglandins, prostaglandin analogs, or prostaglandin derivatives is not recommended.

Systemic Effects: Like other topically applied ophthalmic agents, is absorbed systemically. Due to the beta-adrenergic component timolol, the same types of cardiovascular, pulmonary and other adverse reactions seen with systemic beta-adrenergic blocking agents may occur including aggravation of Prinzmetal’s angina, aggravation of peripheral and central circulatory disorders, bradycardia, and hypotension.

Incidence of systemic adverse drug reactions after topical ophthalmic administration is lower than for systemic administration. The systemic absorption can be reduced by using nasolacrimal occlusion or closing the eyelids for 2 minutes (see DOSAGE AND ADMINISTRATION).

Cardiovascular

Cardiac reactions: Death associated with cardiac failure has been reported. Cardiac failure should be adequately controlled before beginning treatment. Patients with a history of severe cardiac disease should be watched for signs of cardiac failure and have their pulse rates checked. At the first sign of cardiac failure, XALACOM should be discontinued. Due to its negative effect on conduction time, beta-adrenergic blocking agents should only be given with caution to patients with first degree heart block.

Vascular Disorders: Patients with severe peripheral circulatory disturbance/disorders (i.e. severe forms of Raynaud’s disease or Raynaud’s syndrome) should be treated with caution.

Endocrine and Metabolism

Diabetes Mellitus: Beta-adrenergic blocking agents should be administered with caution in patients subjected to spontaneous hypoglycemia or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycemic agents. Beta-adrenergic blocking agents may mask the signs and symptoms of acute hypoglycemia.

Thyrotoxicosis: Therapy with beta-adrenergic blocking agents may mask certain symptoms of hyperthyroidism. Abrupt withdrawal of beta-adrenergic blocking agent therapy may precipitate a worsening of symptoms.

Hepatic/Biliary/Pancreatic

XALACOM has not been studied in patients with hepatic impairment and therefore should be used with caution in such patients.

Neurologic

Muscle Weakness: Beta-adrenergic blocking agents have been reported to rarely increase muscle weakness in some patients with myasthenia gravis or myasthenic symptoms (e.g. diplopia, ptosis, generalized weakness).

Ophthalmologic

Latanoprost has been reported to cause darkening, thickening and lengthening of eye lashes (see ADVERSE REACTIONS).

Based on spontaneous reports, very rare cases of darkening of the palpebral skin have been reported with the administration of latanoprost ophthalmic solution (see ADVERSE REACTIONS).

Due to the prostaglandin component latanoprost, XALACOM should be used with caution in patients with a history of herpetic keratitis. XALACOM should be avoided in cases of active herpes simplex keratitis and in patients with a history of recurrent herpetic keratitis specifically associated with prostaglandin analogues.

This product contains benzalkonium chloride as a preservative, which may be absorbed by soft contact lenses. Remove contact lenses before administration of XALACOM. Contact lenses may be reinstalled 15 minutes after administering XALACOM.

Ophthalmic beta-adrenergic blocking agents may induce dryness of eyes. These agents should be used prescribed with caution in patients with corneal diseases.

Macular edema, including cystoid macular edema, has been reported during treatment with latanoprost ophthalmic solution. These reports have mainly occurred in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema. XALACOM should be used with caution in these patients.

Choroidal detachment after filtration procedures has been reported with the administration of ocular hypotensive agents.

Changes to Pigmented Tissues: Latanoprost, the prostaglandin component contained in XALACOM, may gradually change the eye color, by increasing the amount of brown pigment in the iris. The color change is due to increased melanin content in stromal melanocytes on the iris rather than to an increase in the number of melanocytes. Typically the brown pigmentation around the pupil spreads concentrically towards the periphery in affected eyes, but the entire iris or parts of it may become more brownish. The change in iris colour occurs slowly and may not be noticeable for several months to years. The long term effects on the melanocytes and the consequences of potential injury to the melanocytes and/or deposition of pigment granules to other areas of the eye is currently unknown. Patients should be examined regularly and, depending on the clinical situation, treatment may be stopped if increased iris pigmentation ensues.

This effect has predominantly been seen in patients with mixed colored irides (i.e. blue/gray-brown, green-brown, or yellow-brown). In patients with homogeneously blue, gray, green or brown eyes, the change has only rarely been seen during two years of treatment in clinical trials. The change in iris color occurs slowly, and may not be noticeable for several months to years. Patients should be informed of the possibility of iris color change. Patients who are expected to receive treatment in only one eye should be informed about the potential for increased brown pigmentation in the treated eye and thus, permanent heterochromia between the eyes. The increased pigmentation is permanent.

There is no evidence of melanin from iris melanocytes in trabecular meshwork in clinical studies which supports the lack of hyperpigmentation of the trabecular meshwork as a result of latanoprost treatment. In addition, no difference in iridial pigment epithelial melanin content has been observed between the latanoprost-treated eyes with increased iris pigmentation and untreated eyes from quantitative morphologic investigation of iridial specimens following colour change. Histopathologically, the increase in pigmentation was limited to a minor increase in the size of the melanin granules in the iris stroma.

Closed Angle Glaucoma: XALACOM should not be used alone in the treatment of acute closed angle glaucoma. In patients with closed angle glaucoma, the immediate objective of treatment is to reopen the angle. This requires constricting the pupil. Latanoprost and Timolol Maleate have little or no effect on the pupil.

Peri-Operative Considerations

A gradual withdrawal of beta-adrenergic blocking agents prior to major surgery should be considered. Beta-adrenergic blocking agents impair the ability of the heart to respond to beta-adrenergically mediated reflex stimuli, which may augment the risk of general anesthesia in surgical procedures. Protracted severe hypotension during anesthesia and difficulty restarting and maintaining the heartbeat have been reported. During surgery, the effects of beta-adrenergic blocking agents may be reversed by sufficient doses of adrenergic agonists.

Surgical anaesthesia: Beta-blocking ophthalmological preparations may block systemic beta-agonist effects e.g. of adrenaline. The anaesthesiologist should be informed when the patient is receiving timolol.  

Renal

XALACOM has not been studied in patients with renal impairment and therefore should be used with caution in such patients.

Respiratory

Respiratory Reactions: Severe respiratory reactions including death due to bronchospasm in patients with asthma and rarely death associated with cardiac failure have been reported following administration of beta-adrenergic blocking agents.

Respiratory Disorders: Due to the beta-adrenergic component timolol maleate, XALACOM should be used with caution, in patients with mild/moderate chronic obstructive pulmonary disease (COPD) and only if the potential benefit outweighs the potential risk.

Sensitivity / Resistance

Anaphylactic Reactions: While taking beta-adrenergic blocking agents, patients with a history of atopy or severe anaphylactic reaction to a variety of allergens may be more sensitive to repeated challenge. These could include environmental, diagnostic or therapeutic allergens. Such patients may be unresponsive to the usual doses of adrenaline used to treat anaphylactic reactions.

Sexual Function / Reproduction

Fertility: Latanoprost has not been found to have any effect on male or female fertility in animal studies. Reproduction and fertility studies of timolol maleate in rats demonstrated no adverse effect on male or female fertility at doses up to 21,000 times the systemic exposure following the maximum recommended human ophthalmic dose.

Special Populations

Pregnant Women: No reproduction toxicity studies have been conducted with XALACOM. Embryofetal development studies with latanoprost have been performed in rats and rabbits. Latanoprost and/or its metabolites cross the placenta of rats. In rabbits, latanoprost caused embryofetal toxicity characterized by increased incidences of late resorption and reduced fetal weight at 5 mcg/kg/day IV and total litter resorption at > 50 mcg/kg/day IV. No embryofetal effects were seen in rabbits at 1 mcg/kg/day IV and in rats at up to 250 mcg/kg/day IV.

Timolol maleate was not teratogenic in mice, rats and rabbits. Embryofetal development studies with timolol maleate in mice and rabbits showed no evidence of embryofetal toxicity at oral doses up to 50 mcg/kg/day. At higher doses, increases in resorptions and fetal variations (14 ribs and hypoplastic sternebrae) were noticed in mice (1000 mcg/kg/day) and increased resorption in rabbits (> 90 mcg/kg/day). In rats, delayed ossification was seen ­> 50 mcg/kg/day and a decreased number of caudal vertebral bodies and arches and an increase in hypoplastic sternebrae were noted at 500 mcg/kg/day.

For additional information, see TOXICOLOGY.

XALACOM should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Women: There are limited experimental animal and no human data available on the pharmacokinetics of latanoprost lactation. Latanoprost and its metabolites may pass into breast milk. Timolol maleate has been detected in human milk following oral and ocular administration. Because of the potential for serious adverse reactions from XALACOM in nursing infants, XALACOM should be used with caution in nursing women.

Pediatrics: XALACOM is not recommended for use in children. The safety and efficacy of the use of XALACOM in children has not been established.

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